Grammati Sarri (left), Gill Ritchie, and Grant Hill-Cawthorne describe the role of GPs in testing for chronic hepatitis B and summarise the secondary care treatment pathways


NICE Accreditation Mark

NICE Clinical Guideline 165 on Hepatitis B (chronic): Diagnosis and management of chronic hepatitis B in children, young people and adults has been awarded the NICE Accreditation Mark.

This Mark identifies the most robustly produced guidance available. See evidence.nhs.uk/accreditation for further details.

C hronic hepatitis B is a lifelong condition that is associated with a significant burden of avoidable morbidity or mortality. About a third of the world’s population has serological evidence of past or present hepatitis B virus (HBV) infection, and 350–400 million people have chronic HBV infection.1 In the UK, about 326,000 people are thought to have chronic hepatitis B.2 Effective diagnosis and treatment of chronic HBV infection will reduce transmission of the virus as well as the progression of liver disease and liver cancer. Reducing the mortality rate of people aged under 75 years from liver disease and cancer are highlighted as improvement areas in domain 1 of the NHS Outcomes Framework 2013/14.3

Background

Chronic hepatitis B describes a spectrum of disease usually characterised by the presence of detectable hepatitis B surface antigen (HBsAg) in the blood or serum for longer than 6 months.4,5 In some people, chronic hepatitis B is inactive and does not present significant health problems, but in others it may progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). It is during the ‘immune clearance’ and ‘immune escape’ phases (see Figure 1) that the immune response to virus-infected hepatocytes causes liver damage and progressive fibrosis.6

Hepatitis B e antigen and viral replication

Chronic hepatitis B can be divided into hepatitis B e antigen (HBeAg) positive or HBeAg-negative disease, based on the presence or absence of HBe antigen. The presence of HBeAg is typically associated with higher levels of viraemia and therefore increased infectivity. The level of viraemia can be measured by HBV deoxyribonucleic acid (DNA) assay, and recent evidence indicates that people with the highest levels of viraemia are at greatest risk of developing cirrhosis and HCC.7

Without antiviral treatment, the 5-year cumulative incidence of cirrhosis for all individuals with chronic hepatitis B ranges from 8% to 20%.8 People with cirrhosis who remain untreated face a significant risk of decompensated liver disease. Five-year survival rates among people with untreated decompensated cirrhosis can be as low as 15%.4

Aims of treatment

The goals of treatment for chronic hepatitis B are to prevent cirrhosis, HCC, and liver failure. Antiviral therapy suppresses HBV replication and decreases hepatic inflammation and fibrosis, thereby reducing the likelihood of serious clinical disease.

Since the introduction of effective treatment in the form of interferon alfa, several nucleoside and nucleotide analogues are also now approved for use in adults with chronic hepatitis B, together with a pegylated form of interferon alfa.4 With multiple treatment options that are efficacious and safe, the key questions for healthcare professionals are:4

  • which patients need immediate treatment?
  • what sequence and combination of drug regimens should be used?
  • which patients can be monitored and when can treatment be delayed?
Figure 1: Natural history of chronic hepatitis B infection6
Natural history of chronic hepatitis B infection

HbeAG=hepatitis e antigen; Anti-HBe=hepatitis B e antigen antibody; HBV=hepatitis B virus; DNA=deoxyribonucleic acid; ALT=alanine aminotransferase; ULN=upper limit of normal of ALT.
After Chu C, Karayiannis P, Fowler M et al. Hepatology 1985; 5: 4 31–434

NICE guidance

Guidance on identifying people with chronic hepatitis B in primary care was addressed by recent NICE Public Health guidance, Hepatitis B and C: ways to promote and offer testing (Public Health Guidance 43, see www.nice.org.uk/guidance/PH43), which sets out how services, organisations, and practitioners can promote testing and reach people at increased risk of hepatitis B and C infection.9 General practitioners, who are often the first contact for people at risk of hepatitis B and C, have an important role to play in the identification of those individuals with risk factors for infection, their testing and onward referral to specialist services, and their ongoing care (including monitoring).

NICE Clinical Guideline (CG) 165 on Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults (see www.nice.org.uk/guidance/cg165) was published in June 2013. The key issues covered are:4

  • identification and assessment of chronic hepatitis B, including:
    • healthcare setting for pre-therapeutic tests
    • range of pre-therapeutic testing required
    • criteria for referral to specialist services
    • use of non-invasive testing to reduce the number of liver biopsies required
    • diagnosis of concomitant infections, hepatitis C, and hepatitis delta (D) virus
  • pharmacological treatment with a focus on:
    • sequential and combination drug therapy
    • strategies for prophylactic treatment of patients treated with immunosuppressives
  • monitoring disease stages, which includes discussion on:
    • monitoring of patients on and off treatment
    • HCC surveillance timing and frequency
  • patient information.

In NICE CG165,4 recommendations are made based on the clinical and cost-effectiveness of sequences of drugs and on the necessary frequency of monitoring to detect toxicity and the development of viral resistance, which may require a change in therapy.


Figure 2: chronic hepatitis B management pathway10
chronic hepatitis B management pathway

HCC=hepatocellular carcinoma
National Clinical Guideline Centre. Hepatitis B (chronic). Diagnosis and management of chronic hepatitis B in children, young people and adults. NCGC, 2013. Reproduced with kind permission.

Role of primary care

It is hoped that NICE CG165 will support GPs in their assessment of patients found to be HBsAg positive and guide them in the appropriate investigations to be undertaken. The guidance advises a standard set of tests to be carried out in primary care, as discussed below, and a standard set of criteria for referral to specialist hepatology, gastroenterology, or infectious disease services across England and Wales.4 The guidance also covers the information that should be provided to patients. This should help GPs in their discussions with patients about the risks of other blood-borne viral infections and about the testing, and (as appropriate) the immunisation of family members.

General practitioners and their staff are likely to see people with chronic hepatitis B, and also their immediate and extended families, over long periods of time. The provision of relevant and comprehensive information will help patients to gain an increased understanding of their disease and be better able to make informed decisions about their treatment choices. Four main areas were considered to be important in terms of information provision in this guidance:4

  • prognosis and risk associated with no treatment
  • benefits of treatment
  • side-effects of treatment
  • risk of transmission during different phases (for both treated and untreated people).

Separate recommendations are made to cover the prevention of HBV transmission from mother to babies for pregnant women with high levels of viraemia, and for the prevention of HBV reactivation and fulminant hepatitis for people undergoing immunosuppressive or cancer therapies. The role of primary care includes:

  • the immunisation of babies from HBeAg+ mothers
  • in some areas, the prescription of immunosuppressive therapy—this could include high-dose steroids (e.g. as used for exacerbations of asthma)
  • the ongoing monitoring of people on other immunosuppressives, such as those started by rheumatologists for connective tissue disorders—therefore an understanding and appreciation of who may need prophylaxis is important
  • depending upon the local set-up, the 48-weekly monitoring of alanine transaminase and HBV DNA levels in patients with inactive chronic hepatitis B—many of the monitoring blood tests could also be sent off from primary care or secondary care.

Key priorities for implementation

The key priorities for implementation in NICE CG165 are summarised below.

Assessment in primary care and referral

Adults, children, and young people
Primary care should arrange the following tests for adults, children, and young people who are HBsAg positive:4

  • HBeAg/anti-HBe status
  • HBV DNA level
  • lgM antibody to hepatitis B core antigen (anti-HBc lgM)
  • hepatitis C virus antibody (anti-HCV)
  • hepatitis delta virus antibody (anti-HDV)
  • HIV antibody (anti-HIV)
  • lgG antibody to hepatitis A virus (anti-HAV)
  • additional laboratory tests, including:
    • alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
    • gamma-glutamyl transferase (GGT)
    • serum albumin
    • total bilirubin
    • total globulins
    • full blood count
    • prothrombin time
  • tests for HCC, including hepatic ultrasound and alpha-fetoprotein testing (a hepatic ultrasound should be requested by the GP with the results of this being available to the hospital specialist).

It is recommended that all children, young people, and adults who are HBsAg positive are referred to a paediatric or adult (as appropriate) hepatologist, gastroenterologist, or infectious disease specialist with an interest in hepatology. The patient’s results should be available to the specialist at the time of the first consultation; this will ensure more timely and efficient care for patients and reduce the number of visits to specialist services prior to treatment being commenced.4

Pregnant women
Pregnant women who are HBsAg positive should be referred to a hepatologist, gastroenterologist, or infectious disease specialist with an interest in hepatology for assessment within 6 weeks of receiving a positive screening result, so as to allow treatment in the third trimester.4

Assessment and treatment of adults, young people, and children in secondary care

NICE CG165 recommends transient elastography as the initial test for liver disease in adults following referral to secondary care. The accuracy, limitations, and risks of non-invasive testing versus liver biopsy need to be discussed with the adult patient by a healthcare professional trained in the interpretation of the test findings. The guidance recommends only the use of liver biopsy in children to assess the need of antiviral treatment. NICE CG165 also details the circumstances under which treatment can be started immediately and when confirmation with a liver biopsy may be necessary.4

It is recommended that the treatment of chronic hepatitis B should be started in secondary care; however, the treatment sequence for different patient groups,4 summarised in Box 1 (below), will be useful knowledge for healthcare professionals in primary care.

One key aspect is that the sequences of drug treatment start with peginterferon alfa-2a as an option; peginterferon alfa-2a is given as a single course and this can result in seroconversion without the need for continued treatment, while second-line treatments are usually lifelong. Guidance is provided in CG165 for care plans, information, and support for patients self-injecting peginterferon alfa-2a, together with frequencies for regular monitoring, to help patients adhere to the treatment plan.4 The use of peginterferon alfa-2a in pregnancy is to be avoided unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout peginterferon alfa-2a therapy.

NICE CG1654 should improve and rationalise prescribing in chronic hepatitis B, leading to potentially fewer cases of liver disease and HCC. NICE recommends in CG165 that treatment be initiated only when predictors are present for fibrosis progression, cirrhosis, and HCC, as the use of nucleoside/nucleotide analogues is likely to be lifelong and they work best in people who are mounting an immune response to the virus.

Box 1: Treatment sequences for chronic hepatitis B4

Treatment sequence in adults with HBeAg-positive chronic hepatitis B and compensated liver disease

  • >Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-positive chronic
    hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy
  • Offer tenofovir disoproxil as second-line treatment to people who do not undergo HBeAg seroconversion or who relapse (i.e. revert to being HBeAg positive following seroconversion) after first-line treatment with peginterferon alfa-2a
  • Offer entecavir as an alternative second-line treatment to people who cannot tolerate tenofovir disoproxil or if it is contraindicated.

Treatment sequence in adults with HBeAg-negative chronic hepatitis B and compensated liver disease

  • Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-negative chronic hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy
  • Offer entecavir or tenofovir disoproxil as second-line treatment to people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a.

Treatment sequence in children and young people with chronic hepatitis B and compensated liver disease

  • Offer a 48-week course of peginterferon alfa-2a as first-line treatment in children and young people with chronic hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy
  • Consider a nucleoside or nucleotide analogue as second-line treatment in children and young people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a.

Women who are pregnant or breastfeeding

  • Offer tenofovir disoproxil to women with HBV DNA greater than 107 IU/ml in the third trimester to reduce the risk of transmission of HBV to the baby. At the time of publication of CG165 (June 2013), tenofovir disoproxil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices—guidance for doctors
    (available at
    www.gmc-uk.org/guidance/ethical_guidance/14316.asp) for further information
  • Passive/active vaccination is also required.

Reactivation of hepatitis B associated with immunosuppression

People with evidence of previous infection with hepatitis B virus (anti-HBc positive) may experience viral reactivation when their immune system is suppressed as part of the treatment for autoimmune or atopic diseases, cancer chemotherapy, bone marrow or solid organ transplantation. Screening these people for antibody to the hepatitis B surface antigen (anti-HBs), raised plasma or serum HBV DNA levels, or raised ALT will help to quantify their risk for viral reactivation. For patients at risk, the prophylaxis recommended is shown in Box 2.4

Box 2: Prophylactic treatment during immunosuppressive therapy 4

  • In people who are HBsAg positive and have HBV DNA greater than 2000 IU/ml, offer prophylaxis with entecavir11* or tenofovir disoproxil:12*
    • start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after HBeAg seroconversion and
      HBV DNA is undetectable
  • In people who are HBsAg positive and who have HBV DNA less than
    2000 IU/ml, offer prophylaxis:
    • consider lamivudine13* if immunosuppressive therapy is expected to last less than 6 months
    • monitor HBV DNA monthly in people treated with lamivudine13* and change to tenofovir disoproxil12* if HBV DNA remains detectable after
      3 months
    • consider entecavir11* or tenofovir disoproxil12* if immunosuppressive therapy is expected to last longer than 6 months
    • start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after stopping immunosuppressive therapy.

HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; DNA= deoxyribonucleic acid

*At the time of publication of CG165 (June 2013), entecavir, lamivudine, and tenofovir disoproxil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices—guidance for doctors (www.gmc-uk.org/guidance/ethical_guidance/14316.asp) NHS Trust, 2012.

Implementation of the guideline

Chronic hepatitis B is under-diagnosed in the UK. It is essential, therefore, that CG165 is read in association with the NICE public health recommendations on improving case identification of HBV and HCV.9 We recommend that essential serological tests are performed in primary care and that the results accompany the patient to the specialist to ensure more timely and efficient care. The availability of tests to GPs may vary, but clinical commissioning groups should be able to ensure that appropriate access to laboratory tests is available. The prevalence of hepatitis B will vary according to the population of an area, and in some areas the costs of these tests and treatments may be significant.

Conclusion

General practitioners have a pivotal role in the initial assessment, referral, and monitoring of patients with chronic hepatitis B. Primary care is the first contact point for provision of valuable information regarding the natural history of disease, family planning, transmission routes, and choices of treatments with associated benefits and risks. Providing the correct information to patients, as well as ensuring that those at risk of long-term liver disease are promptly referred with all necessary testing completed, will enhance the care provided to patients with chronic hepatitis B.

NICE implementation tools

>NICE has developed the following tools to support implementation of Clinical Guideline 165 (CG165) on Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. The tools are now available to download from the NICE website: www.nice.org.uk/CG165

NICE support for commissioners

Costing templateCommissioning.eps

A costing template helps services in estimating the local cost of implementing guidelines and public health guidance. This template allows individual NHS organisations and local health economies to quickly assess the impact guidance will have on local budgets.

NICE support for service improvement systems and audit

Baseline assessment toolAudit.eps

The baseline assessment tool is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.

Clinical audit toolAudit.eps

Clinical audit tools aim to assist organisations with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. They consist of audit criteria and data collection tool(s) and can be edited or adapted for local use.

Key to NICE implementation icons

Commissioning.epsNICE support for commissioners

  • Support package for commissioners and others for quality standards
  • NICE guide for commissioners
  • NICE cost impact support for guidance (selection from national report/local template/costing statement, dependent on topic)

Audit.epsNICE support for service improvement systems and audit

  • Forward planner
  • 'How to' guides (generic advice on processes)
  • Local government briefings (with Centre for Public Health Excellence)
  • Baseline assessment tool for guidance
  • Audit support including electronic data collection tools
  • E-learning modules (commissioned)

Education.epsNICE support for education and learning

  • Clinical case scenarios
  • Learning packages including slide sets
  • Podcasts
  • Shared learning and other local best practice examples

Acknowledgements

The authors wish to thank the following people for their contribution to this manuscript: Professor Howard Thomas, Elisabetta Fenu, Amy Kelsey, Dr Allan Mitchell, Maggie Westby. Lastly, we are grateful to Dr Norma O’Flynn for commenting on earlier versions of this article.

References

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  2. Hepatitis B Foundation UK website. Rising curve: chronic hepatitis B infection in the UK. Hepatitis B Foundation, 2008. www.hepb.org.uk/information/resources/rising_curve_chronic_hepatitis_b_infection_in_the_uk
  3. Department of Health. The NHS outcomes framework 2013/2014. DH, 2012. Available at: www.gov.uk/government/uploads/system/uploads/attachment_data/file/213055/121109-NHS-Outcomes-Framework-2013-14.pdf
  4. NICE. Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. Clinical Guideline 165. NICE, 2013. Available at: www.nice.org.uk/guidance/CG165nhs_accreditation
  5. Ganem D, Prince A. Hepatitis B virus infection: natural history and clinical consequences. N Engl J Med 2004; 350 (11): 1118–1129.
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  9. NICE. Hepatitis B and C: ways to promote and offer testing. Public Health Guidance 43. NICE, 2012. Available at: www.nice.org.uk/guidance/PH43 www.nice.org.uk/guidance/PH43nhs_accreditation
  10. National Clinical Guideline Centre. Hepatitis B (chronic). Diagnosis and management of chronic hepatitis B in children, young people and adults. NCGC, 2013. Available at: www.nice.org.uk/nicemedia/live/14191/64248/64248.pdf
  11. Bristol-Myers Squibb Pharmaceutical Limited. Baraclude 0.5 mg and 1.0 mg film-coated tablets and Baraclude 0.05 mg/ml oral solution—summary of product characteristics.www.medicines.org.uk/emc/medicine/18377/SPC/Baraclude++0.5+mg+and+1.0+mg+
    film+coated+tablets+and+Baraclude+0.05mg+ml+oral+solution/
    (accessed 22 October 2013).
  12. Gilead Sciences Ltd. Viread 245 mg film-coated tablets—summary of product characteristics. www.medicines.org.uk/emc/medicine/9008/SPC/Viread+245+mg+film-coated+tablets/ (accessed 5 November 2013).
  13. ViiV Healthcare UK Ltd. Epivir 300 mg tablets—summary of product characteristics. www.medicines.org.uk/emc/medicine/8131/SPC/Epivir+300mg+Tablets/ (accessed
    22 October 2013). G